A number of pathogens cause chronic infections. Various viruses, fungi and bacteria, for example, can cause persistent infections that fail to resolve.
As the number of severe fungal infections continues to rise, the need for methods and compositions for their treatment is more urgent. Major fungal pathogens include Candida albicans, Aspergillus fumigatus and Cryptococcus neoformans, with estimated annual incidence for invasive mycoses involving these pathogens of 72-228 (for Candida species), 12-34 (for Aspergillus species) and 30-66 (for C. neoformans) infections per million population in the United States. Pfaller et al. (2006) Clin. Infect. Dis. 43:S3-14. The rise in fungal infections is primarily due to the increasing number of immuno-compromised patients as a result of medical advances (transplantation and chemotherapy), and as a result of the increasing population of AIDS patients. More than 80% of fungal infections in immunocompromised patients are caused by Candida species. Cryptococcosis is the second most prevalent fungal infection in AIDS patients following candidiasis. Aspergillosis is responsible for at least 30% of the infections in cancer and organ transplant patients and has a high mortality rate.
Although fluconazole has been an effective drug against fungal pathogens for a number of years, resistance is increasing. Alternatives such as amphotericin B have serious drawbacks, including such side effects as fever, kidney damage, anemia, low blood pressure, headache, nausea, vomiting and phlebitis.
Bacterial infections remain an important issue despite the prevalence of antibiotics, in light of an increased population of immune compromised individuals and a widespread development of antibiotic resistant bacterial strains. Immune compromised individuals include the elderly, transplant recipients, chemotherapy patients, and individuals with acquired immune deficiency syndrome (AIDS). Nearly two million patients in the United States get an infection in the hospital each year, and 70% of the bacteria responsible for those infections are resistant to at least one antibiotic. NIAID Fact Sheet, “The Problem of Antimicrobial Resistance,” April 2006. In recent years, about 90,000 people in the United States die from infections, up from 13,300 in 1992. Although most bacterial infections remain susceptible to a prolonged course of therapy of at least one antibiotic (e.g. continuous intravenous administration of vancomycin), there is no guarantee that this will remain true with future pathogenic bacteria. Methicillin resistant Stapholococcus aureus (MRSA) is a prime example of a multiple-antibiotic-resistant microbe that represents a significant public health challenge. In 2002, the Centers for Disease Control (CDC) reported the first case of a S. aureus infection that was completely resistant to vancomycin (dubbed VRSA) in a patient in Michigan. Persistent bacterial pathogens also include Salmonella spp., Brucella spp. and Chlamydia spp.
Mycobacteria are a diverse and widely distributed group of aerobic, nonsportulating, nonmotile bacilli that have a high cell-wall lipid content and a slow growth rate. Members of the genus Mycobacterium vary in virulence, e.g., from harmless to species with significant pathogenicity, for example, M. tuberculosis, the causative agent in tuberculosis (TB). TB is the second leading infectious cause of death in the world. It is estimated that about two billion people, or one third of the world's population, are infected with M. tuberculosis. Eight million new cases and nearly three million deaths occur annually. TB is directly responsible for 7% of all deaths world wide, and the global epidemic is likely to worsen as a result of the spread of drug-resistant organisms and the ongoing HIV epidemic. See, e.g., Dale and Federman (eds.) (2002) WebMD Scientific American Medicine, WebMD Professional Publishing, New York, N.Y.
Most current methods to treat TB involve the use of broad spectrum anti-infective agents such as isoniazid, rifampin, pyrazinamide, ethambutol, streptomycin, ciprofloxacin, and ofloxacin. Such agents, however, can cause toxicities in various organs, and with the growth of several antibiotic resistant strains of TB, are losing efficaciousness. Reducing the mycobacterial burden in the lungs of tuberculosis patients with the use of a variety of non-antibiotic agents can prevent disease formation, transmission, and death.
Chronic viral infections also represent a significant threat to public health. Failure to completely eradicate viral infections such as hepatitis C virus (HCV) or human immunodeficiency virus (HIV) can lead to subsequent reactivations and complications such as liver cancer or acquired immune deficiency syndrome (AIDS), respectively. Robertson & Hasenkrug (2006) Springer Semin. Immun. 28:51. In addition, human papillomavirus (HPV) genotypes 16, 18, 31, 33, 45, and 56 account for more than 95% of cases of cervical cancer. Berzofsky et al. (2004) J. Clin. Invest. 114:450. It is estimated that chronic infections arise in virtually 100% of cases of HIV infection, 55-85% of cases of HCV infection, and over 30% of cases of HPV. Berzofsky et al. (2004).
The need exists for improved methods and compositions for treatment and/or prevention of bacterial, viral and fungal infections. Such methods and compositions are preferably less toxic and/or more efficacious that existing treatment methods and compositions.